We have recently demonstrated that p202, an interferon-inducible protein, mediates multiple anti-tumor activities in a pancreatic orthotopic animal model. Specifically, we have demonstrated that p202 expression is associated with many potential anti-tumor activities, including inhibition of tumor growth, reduced tumorigenecity, prolonged survival, and remarkably, suppression of metastasis and angiogenesis. An in vitro invasion assay also showed that p202-expressing pancreatic cancer cells are less invasive than those without p202 expression. It suggests that the p202 gene may be used to suppress the development of pancreatic cancer in a gene therapy setting. To achieve our goal of developing effective gene therapy for pancreatic cancer, we also have recently developed a stabilized nonviral gene delivery system, SN, that can deliver a therapeutic gene through i.v. injection to effectively suppress the development of both mammary tumors and prostate cancer in orthotopic animal models. In a series of preliminary studies, we have initiated experiments to demonstrate treatment efficacy by using the p202/SN liposome complex in a nude mice xenograft model. These studies suggest the feasibility of using the p202/SN liposome, or gene therapies derived from this approach and described in this project in future preclinical gene therapy experiments. The long-term goal of this project is to develop a novel, effective therapeutic approach to treat pancreatic cancer. Specifically, we would like to first establish strategies using gene therapy via liposome/adenoviral delivery systems in orthotopic animal models as a prelude to clinical translation. To achieve this goal, three specific aims are proposed: (1) To continue preclinical gene therapy experiments using orthotopic animal models of pancreatic cancer to establish a therapeutically effective approach. (2) To identify pancreatic cancer-specific expression/delivery vectors in order to selectively express the therapeutic gene in pancreatic cancer cells, thereby preferentially inhibiting pancreatic cancer cell growth. (3) To evaluate the therapeutic efficacy of combined gene therapy and conventional chemotherapy or radiation therapy. Success of this project will ensure that we are able to initiate a phase I clinical trial within the initial funding period of the Spore application.